The ErbB2 gene product, which is a member of the ErbB family of receptor tyrosine kinases, is believed to play an important role in the malignancy of tumor cells. Studies have shown that the over-expression of ErbB2 causes cell transformation and tumorgenesis, and in vitro experiments have shown that ErbB2 is required for induction of carcinoma cell invasion by other members of the ErbB family. The benzoquinone ansamycin, geldanamycin, has anti-tumor activity in vivo, and has been shown to cause the rapid depletion of ErbB2 protein levels. Geldanamycin is a specific inhibitor of certain chaperone proteins including the heat shock protein-90 (Hsp90) as well as the glucose-regulated protein-94 (Grp94), which is localized to the endoplasmic reticulum. It is believed that geldanamycin acts on the ErbB2 protein through its inhibition of the Hsp90 chaperone protein, which is thought to be necessary for proper function of the ErbB2 protein. Hsp90 also has been shown to be linked to tumor cell proliferation (see L. Whitesell et al., Inhibition of Heat Shock Protein HSP-90-pp60v-src Heteroprotein Complex Formation by Benzoquinone Ansamycins: Essential Role for Stress Proteins in Oncogenic Transformation, 91 Proc. Nat'l Acad. Sci. USA 8324-8328 (1994); T. W. Schulte et al., Antibiotic Radicicol Binds to the N-terminal Domain of Hsp90 and Shares Important Biologic Activities with Geldanamycin, 3 Cell Stress and Chaperone Proteins 100-108 (1998); J. L. Johnson et al., Binding of p23 and Hsp90 During Assembly with the Progesterone Receptor, 9 Mol. Endocrinol. 670-678 (1995); W. Sullivan et al., Nucleotides and two functional states of Hsp90, 272 J. Biol. Chem. 8007-8012 (1997)).
Analogues of geldanamycin have been synthesized in attempts to increase the bioavailability and reduce the toxicity associated with the natural product. Among the more successful analogues is 17-allylaminogeldanamycin (17-AAG), which is currently in phase I clinical trials at the National Cancer Institute. Other similar geldanamycin derivatives substituted at the 17th position exist as possible cancer treatments, such as those described in R. C. Schnur et al., Inhibition of the Oncogene Product p185erB-2 in Vitro and in Vivo by Gedanamycin and Dihydrogeldanamycin Derivatives, 38 J. Med. Chem. 3806-3812 (1995). While many of these compounds show relatively significant activity in vitro, few exhibit sufficient in vivo activity in preliminary testing. Thus, these compounds represent poor candidates as a potential means of therapeutic treatment. In addition, no known geldanamycin compound or derivative thereof has shown in vivo activity when administered orally.
Thus, a need remains for other effective anticancer compounds and methods of using such compounds. The present invention seeks to fulfill such a need. The particular advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.